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PURPOSE: Leptomeningeal metastases (LM) are an aggressive complication of metastatic breast cancer (MBC) with brain metastases (BM), with a short survival of weeks to months. Studies suggest that surgical resection of BM may increase the risk of LM, especially in infratentorial metastases. In this retrospective study, we examine this and other factors which may be associated with increased risk of LM. METHODS: A database search at a single institution identified 178 patients with MBC and treated BM between 2007 and 2020. We collected demographic, clinical, radiographic, and other treatment data. LM was diagnosed by cerebrospinal fluid (CSF) cytology, neuroimaging, or both. Cox proportional hazards model was used. RESULTS: After a median follow-up of 8.5 months, 41 out of 178 patients (23%) with BM developed LM. Median time to develop LM was 130 days. Mean age was 51.3 years. The number and size of the BM, hemorrhagic/cystic lesions, progressive/stable systemic disease, and extracranial metastases sites other than liver did not pose a higher risk of LM. Infratentorial lesions (HR = 5.41) and liver metastases (HR = 2.28) had a higher risk of LM. Patients who had any surgery did not have a higher risk for LM (HR 1.13). The LM group had a worse overall survival as compared to the non-LM group. CONCLUSION: Among MBC patients with BM, infratentorial BM and visceral liver lesions increase the risk of LM, whereas local treatment modalities such as surgery and radiation do not. These data imply that local treatment strategy should not differ based on potential risk for LM.
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Neoplasias Encefálicas , Neoplasias de la Mama , Carcinomatosis Meníngea , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/terapia , Neoplasias de la Mama/patología , Femenino , Humanos , Carcinomatosis Meníngea/secundario , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios RetrospectivosRESUMEN
PURPOSE: CXCR1, one of the receptors for CXCL8, has been identified as a druggable target on breast cancer cancer stem cells (CSC). Reparixin (R), an investigational oral inhibitor of CXCR1, was safely administered to metastatic breast cancer patients in combination with paclitaxel (P) and appeared to reduce CSC in a window-of-opportunity trial in operable breast cancer. The fRida trial (NCT02370238) evaluated the addition of R to weekly as first-line therapy for metastatic (m) TNBC. SUBJECTS AND METHODS: Subjects with untreated mTNBC were randomized 1:1 to R or placebo days 1-21 in combination with weekly P 80 mg/m2 on days 1, 8, 15 of 28-day cycles. The primary endpoint was PFS by central review. RESULTS: 123 subjects were randomized (62 to R + P and 61 to placebo + P). PFS was not different between the 2 groups (median 5.5 and 5.6 months for R + P and placebo + P, respectively; HR 1.13, p = 0.5996). ALDH+ and CD24-/CD44+ CSC centrally evaluated by IHC were found in 16 and 34 of the 54 subjects who provided a metastatic tissue biopsy at study entry. Serious adverse events (21.3 and 20% of subjects) and grade ≥ 3 adverse reactions (ADR) (9.1 and 6.3% of all ADRs) occurred at similar frequency in both groups. CONCLUSION: fRida is the first randomized, double-blind clinical trial of a CSC-targeting agent in combination with chemotherapy in breast cancer. The primary endpoint of prolonged PFS was not met. CLINICAL TRIAL REGISTRATION/DATE OF REGISTRATION: NCT01861054/February 24, 2015.
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Neoplasias de la Mama Triple Negativas , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Femenino , Humanos , Paclitaxel/efectos adversos , Sulfonamidas , Neoplasias de la Mama Triple Negativas/tratamiento farmacológicoRESUMEN
Metaplastic breast cancer (MpBC) is an exceedingly rare breast cancer variant that is therapeutically challenging and aggressive. MpBC is defined by the histological presence of at least two cellular types, typically epithelial and mesenchymal components. This variant harbors a triple-negative breast cancer (TNBC) phenotype, yet has a worse prognosis and decreased survival compared to TNBC. There are currently no standardized treatment guidelines specifically for MpBC. However, prior studies have found that MpBC typically has molecular alterations in epithelial-to-mesenchymal transition, amplification of epidermal growth factor receptor, PI3K/Akt signaling, nitric oxide signaling, Wnt/ß-catenin signaling, altered immune response, and cell cycle dysregulation. Some of these molecular alterations have been studied as therapeutic targets, in both the preclinical and clinical setting. This current review discusses the histological organization and cellular origins of MpBC, molecular alterations, the role of radiation therapy, and current clinical trials for MpBC.
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Neoplasias de la Mama/patología , Transición Epitelial-Mesenquimal , Genes Relacionados con las Neoplasias/genética , Metaplasia/patología , Neoplasias de la Mama Triple Negativas/patología , Vía de Señalización Wnt , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/terapia , Línea Celular Tumoral , Femenino , Humanos , Metaplasia/genética , Metaplasia/metabolismo , Metaplasia/terapia , Terapia Molecular Dirigida/métodos , Óxido Nítrico Sintasa/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/terapiaRESUMEN
BACKGROUND: Cancer stem cells (CSCs) are purported to be responsible for tumor initiation, treatment resistance, disease recurrence, and metastasis. CXCR1, one of the receptors for CXCL8, was identified on breast cancer (BC) CSCs. Reparixin, an investigational allosteric inhibitor of CXCR1, reduced the CSC content of human BC xenograft in mice. METHODS: In this multicenter, single-arm trial, women with HER-2-negative operable BC received reparixin oral tablets 1000 mg three times daily for 21 days before surgery. Primary objectives evaluated the safety of reparixin and the effects of reparixin on CSC and tumor microenvironment in core biopsies taken at baseline and at treatment completion. Signal of activity was defined as a reduction of ≥ 20% in ALDH+ or CD24-/CD44+ CSC by flow cytometry, with consistent reduction by immunohistochemistry. RESULTS: Twenty patients were enrolled and completed the study. There were no serious adverse reactions. CSC markers ALDH+ and CD24-/CD44+ measured by flow cytometry decreased by ≥ 20% in 4/17 and 9/17 evaluable patients, respectively. However, these results could not be confirmed by immunofluorescence due to the very low number of CSC. CONCLUSIONS: Reparixin appeared safe and well-tolerated. CSCs were reduced in several patients as measured by flow cytometry, suggesting targeting of CXCR1 on CSC. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, NCT01861054. Registered on April 18, 2013.
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Neoplasias de la Mama/tratamiento farmacológico , Células Madre Neoplásicas/patología , Receptor ErbB-2/metabolismo , Receptores de Interleucina-8A/antagonistas & inhibidores , Receptores de Interleucina-8B/antagonistas & inhibidores , Sulfonamidas/uso terapéutico , Adulto , Anciano , Animales , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Femenino , Humanos , Ratones , Persona de Mediana Edad , Células Madre Neoplásicas/efectos de los fármacos , Seguridad del Paciente , Sulfonamidas/farmacocinética , Distribución TisularRESUMEN
BACKGROUND: The human epidermal growth factor receptor (HER) family, notably EGFR, is overexpressed in most triple-negative breast cancer (TNBC) cases and provides cancer cells with compensatory signals that greatly contribute to the survival and development of resistance in response to therapy. This study investigated the effects of Pan-HER (Symphogen, Ballerup, Denmark), a novel mixture of six monoclonal antibodies directed against members of the HER family EGFR, HER2, and HER3, in a preclinical trial of TNBC patient-derived xenografts (PDXs). METHODS: Fifteen low passage TNBC PDX tumor samples were transferred into the right mammary fat pad of mice for engraftment. When tumors reached an average size of 100-200 mm3, mice were randomized (n ≥ 6 per group) and treated following three 1-week cycles consisting of three times/week intraperitoneal (IP) injection of either formulation buffer (vehicle control) or Pan-HER (50 mg/kg). At the end of treatment, tumors were collected for Western blot, RNA, and immunohistochemistry analyses. RESULTS: All 15 TNBC PDXs were responsive to Pan-HER treatment, showing significant reductions in tumor growth consistent with Pan-HER-mediated tumor downmodulation of EGFR and HER3 protein levels and significantly decreased activation of associated HER family signaling pathways AKT and ERK. Tumor regression was observed in five of the models, which corresponded to those PDX tumor models with the highest level of HER family activation. CONCLUSIONS: The marked effect of Pan-HER in numerous HER family-dependent TNBC PDX models justifies further studies of Pan-HER in TNBC clinical trials as a potential therapeutic option.
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Anticuerpos Monoclonales/farmacología , Receptor ErbB-2/antagonistas & inhibidores , Receptor ErbB-3/antagonistas & inhibidores , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Animales , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Femenino , Humanos , Ratones , Terapia Molecular Dirigida , Mutación , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptor ErbB-3/genética , Receptor ErbB-3/metabolismo , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Células Tumorales CultivadasRESUMEN
An amendment to this paper has been published and can be accessed via the original article.
RESUMEN
PURPOSE: Capecitabine is important in breast cancer treatment but causes diarrhea and hand-foot syndrome (HFS), affecting adherence and quality of life. We sought to identify pharmacogenomic predictors of capecitabine toxicity using a novel monitoring tool. METHODS: Patients with metastatic breast cancer were prospectively treated with capecitabine (2000 mg/m2/day, 14 days on/7 off). Patients completed in-person toxicity questionnaires (day 1/cycle) and automated phone-in assessments (days 8, 15). Correlation of genotypes with early and overall toxicity was the primary endpoint. RESULTS: Two hundred and fifty-nine patients were enrolled (14 institutions). Diarrhea and HFS occurred in 52% (17% grade 3) and 69% (9% grade 3), respectively. Only 29% of patients completed four cycles without dose reduction/interruption. In 39%, the highest toxicity grade was captured via phone. Three single nucleotide polymorphisms (SNPs) associated with diarrhea-DPYD*5 (odds ratio [OR] 4.9; P = 0.0005), a MTHFR missense SNP (OR 3.3; P = 0.02), and a SNP upstream of MTRR (OR 3.0; P = 0.03). GWAS elucidated a novel HFS SNP (OR 3.0; P = 0.0007) near TNFSF4 (OX40L), a gene implicated in autoimmunity including autoimmune skin diseases never before implicated in HFS. Genotype-gene expression analyses of skin tissues identified rs11158568 (associated with HFS via GWAS) with expression of CHURC1, a transcriptional activator controlling fibroblast growth factor (beta = - 0.74; P = 1.46 × 10-23), representing a previously unidentified mechanism for HFS. CONCLUSIONS: This is the first cancer pharmacogenomic study to use phone-in self-reporting, permitting augmented toxicity characterization. Three germline toxicity SNPs were replicated, and several novel SNPs/genes having strong functional relevance were discovered. If further validated, these markers could permit personalized capecitabine dosing.
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Antimetabolitos Antineoplásicos/efectos adversos , Biomarcadores de Tumor/genética , Neoplasias de la Mama/patología , Capecitabina/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/genética , Femenino , Ferredoxina-NADP Reductasa/genética , Estudios de Seguimiento , Genotipo , Mutación de Línea Germinal , Humanos , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Pronóstico , Estudios Prospectivos , Calidad de VidaRESUMEN
Cancer cells induce a set of adaptive response pathways to survive in the face of stressors due to inadequate vascularization. One such adaptive pathway is the unfolded protein (UPR) or endoplasmic reticulum (ER) stress response mediated in part by the ER-localized transmembrane sensor IRE1 (ref. 2) and its substrate XBP1 (ref. 3). Previous studies report UPR activation in various human tumours, but the role of XBP1 in cancer progression in mammary epithelial cells is largely unknown. Triple-negative breast cancer (TNBC)--a form of breast cancer in which tumour cells do not express the genes for oestrogen receptor, progesterone receptor and HER2 (also called ERBB2 or NEU)--is a highly aggressive malignancy with limited treatment options. Here we report that XBP1 is activated in TNBC and has a pivotal role in the tumorigenicity and progression of this human breast cancer subtype. In breast cancer cell line models, depletion of XBP1 inhibited tumour growth and tumour relapse and reduced the CD44(high)CD24(low) population. Hypoxia-inducing factor 1α (HIF1α) is known to be hyperactivated in TNBCs. Genome-wide mapping of the XBP1 transcriptional regulatory network revealed that XBP1 drives TNBC tumorigenicity by assembling a transcriptional complex with HIF1α that regulates the expression of HIF1α targets via the recruitment of RNA polymerase II. Analysis of independent cohorts of patients with TNBC revealed a specific XBP1 gene expression signature that was highly correlated with HIF1α and hypoxia-driven signatures and that strongly associated with poor prognosis. Our findings reveal a key function for the XBP1 branch of the UPR in TNBC and indicate that targeting this pathway may offer alternative treatment strategies for this aggressive subtype of breast cancer.
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Proteínas de Unión al ADN/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Factores de Transcripción/metabolismo , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Animales , Antígeno CD24/metabolismo , Hipoxia de la Célula/genética , Línea Celular Tumoral , Proliferación Celular , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Progresión de la Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Silenciador del Gen , Humanos , Receptores de Hialuranos/metabolismo , Ratones , Invasividad Neoplásica , Recurrencia Local de Neoplasia , Pronóstico , ARN Polimerasa II/metabolismo , Factores de Transcripción del Factor Regulador X , Factores de Transcripción/deficiencia , Factores de Transcripción/genética , Transcripción Genética , Neoplasias de la Mama Triple Negativas/irrigación sanguínea , Neoplasias de la Mama Triple Negativas/genética , Respuesta de Proteína Desplegada , Proteína 1 de Unión a la X-BoxRESUMEN
Metastatic triple-negative breast cancer (mTNBC) patients tend to have a poor overall survival. The primary goals of treatment focus on palliation of symptoms and improvement in overall survival (OS). Single-agent sequential chemotherapy with anthracycline or taxane has remained the cornerstone of treatment for many years. The FDA has approved newer agents such as poly-adenosine diphosphate-ribose polymerase (PARP) inhibitors upfront in germline BRCA (gBRCA) 1/2 mutation carriers; atezolizumab and nab-paclitaxel combination frontline in patients with PD-L1 expression > 1%; and sacituzumab govitecan (IMMU-132), an antibody-drug conjugate in heavily pretreated mTNBC patients.
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Neoplasias de la Mama Triple Negativas , Humanos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológicoRESUMEN
BACKGROUND: Neoadjuvant dual human epidermal growth factor receptor (HER2) blockade with trastuzumab and pertuzumab plus paclitaxel leads to an overall pathologic complete response (pCR) rate of 46%. Dual HER2 blockade with ado-trastuzumab emtansine (T-DM1) and lapatinib plus nab-paclitaxel has shown efficacy in patients with metastatic HER2-positive breast cancer. To test neoadjuvant effectiveness of this regimen, an open-label, multicenter, randomized, phase II trial was conducted comparing T-DM1, lapatinib, and nab-paclitaxel with trastuzumab, pertuzumab, and paclitaxel in patients with early-stage HER2-positive breast cancer. METHODS: Stratification by estrogen receptor (ER) status occurred prior to randomization. Patients in the experimental arm received 6 weeks of targeted therapies (T-DM1 and lapatinib) followed by T-DM1 every 3 weeks, lapatinib daily, and nab-paclitaxel weekly for 12 weeks. In the standard arm, patients received 6 weeks of trastuzumab and pertuzumab followed by trastuzumab weekly, pertuzumab every 3 weeks, and paclitaxel weekly for 12 weeks. The primary objective was to evaluate the proportion of patients with residual cancer burden (RCB) 0 or I. Key secondary objectives included pCR rate, safety, and change in tumor size at 6 weeks. Hypothesis-generating correlative assessments were also performed. RESULTS: The 30 evaluable patients were well-balanced in patient and tumor characteristics. The proportion of patients with RCB 0 or I was higher in the experimental arm (100% vs. 62.5% in the standard arm, p = 0.0035). In the ER-positive subset, all patients in the experimental arm achieved RCB 0-I versus 25% in the standard arm (p = 0.0035). Adverse events were similar between the two arms. CONCLUSION: In early-stage HER2-positive breast cancer, the neoadjuvant treatment with T-DM1, lapatinib, and nab-paclitaxel was more effective than the standard treatment, particularly in the ER-positive cohort. TRIAL REGISTRATION: Clinicaltrials.gov NCT02073487 , February 27, 2014.
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Ado-Trastuzumab Emtansina/uso terapéutico , Albúminas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Lapatinib/uso terapéutico , Paclitaxel/uso terapéutico , Receptor ErbB-2/antagonistas & inhibidores , Ado-Trastuzumab Emtansina/administración & dosificación , Ado-Trastuzumab Emtansina/efectos adversos , Adulto , Anciano , Albúminas/administración & dosificación , Albúminas/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor/análisis , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Femenino , Humanos , Lapatinib/administración & dosificación , Lapatinib/efectos adversos , Persona de Mediana Edad , Terapia Neoadyuvante , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Receptor ErbB-2/metabolismo , Resultado del Tratamiento , Carga Tumoral/efectos de los fármacosRESUMEN
PURPOSE: Limited knowledge exists on the detection of breast cancer stem cell (BCSC)-related mutations in circulating free DNA (cfDNA) from patients with advanced cancers. Identification of new cancer biomarkers may allow for earlier detection of disease progression and treatment strategy modifications. METHODS: We conducted a prospective study to determine the feasibility and prognostic utility of droplet digital polymerase chain reaction (ddPCR)-based BCSC gene mutation analysis of cfDNA in patients with breast cancer. RESULTS: Detection of quantitative BCSC gene mutation in cfDNA by ddPCR mirrors disease progression and thus may represent a valuable and cost-effective measure of tumor burden. We have previously shown that hematological and neurological expressed 1-like (HN1L), ribosomal protein L39 (RPL39), and myeloid leukemia factor 2 (MLF2) are novel targets for BCSC self-renewal, and targeting these genetic alterations could be useful for personalized genomic-based therapy. CONCLUSION: BCSC mutation detection in cfDNA may have important implications for diagnosis, prognosis, and serial monitoring.
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Biomarcadores de Tumor , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Transformación Celular Neoplásica/genética , ADN Tumoral Circulante , Mutación , Células Madre Neoplásicas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/sangre , Neoplasias de la Mama/mortalidad , Análisis Mutacional de ADN , Progresión de la Enfermedad , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Persona de Mediana Edad , Clasificación del Tumor , Metástasis de la Neoplasia , Estadificación de Neoplasias , PronósticoRESUMEN
PURPOSE: This study was aimed to determine the impact of hydroxytyrosol (HT), a minor compound found in olive oil, on breast cancer stem cells (BCSCs) and the migration capacity of triple-negative breast cancer (TNBC) cell lines through the alteration of epithelial-to-mesenchymal transition (EMT) and embryonic signaling pathways. METHODS: BCSCs self-renewal was determined by the mammosphere-forming efficiency in SUM159PT, BT549, MDA-MB-231 and Hs578T TNBC cell lines. Flow cytometric analysis of CD44+/CD24-/low and aldehyde dehydrogenase positive (ALDH+) subpopulations, migration by the "wound healing assay", invasion and Western blot of EMT markers and TGFß signaling were investigated in SUM159PT, BT549 and MDA-MB-231 cell lines. Wnt/ß-catenin signaling was assessed by Western blot in BT549 cells expressing WNT1 and MDA-MB-231 cells. Changes in TGFß activity was determined by SMAD Binding Element (SBE) reporter assay. RESULTS: HT reduced BCSCs self-renewal, ALDH+ (aldehyde dehydrogenase) and CD44+/CD24-/low subpopulations, tumor cell migration and invasion. Consistently, HT suppressed Wnt/ß-catenin signaling by decreasing p-LRP6, LRP6, ß-catenin and cyclin D1 protein expression and the EMT markers SLUG, ZEB1, SNAIL and VIMENTIN. Finally, HT inhibited p-SMAD2/3 and SMAD2/3 in SUM159PT, BT549 and MDA-MB-231 cells, what was correlated with a less TGFß activity. CONCLUSION: In conclusion, we report for the first time the inhibitory role of HT on BCSCs and tumor cell migration by targeting EMT, Wnt/ß-catenin and TGFß signaling pathways. Our findings highlight the importance of the chemopreventive compound HT as a novel candidate to be investigated as an alternative targeted therapy for TNBC.
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Transición Epitelial-Mesenquimal/efectos de los fármacos , Células Madre Neoplásicas/efectos de los fármacos , Alcohol Feniletílico/análogos & derivados , Factor de Crecimiento Transformador beta/efectos de los fármacos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Vía de Señalización Wnt/efectos de los fármacos , beta Catenina/efectos de los fármacos , Antioxidantes/farmacología , Western Blotting , Citometría de Flujo , Humanos , Alcohol Feniletílico/farmacología , Células Tumorales CultivadasRESUMEN
Invasive micropapillary carcinoma (IMPC) is an uncommon variant of breast cancer. Previous studies demonstrated this subtype is often hormone receptor (HR)-positive, resulting in survival outcomes similar to invasive ductal carcinoma. However, many of these studies were conducted prior to HER2 testing availability. We aim to determine the impact of molecular marker status (including HER2 status) on IMPC survival outcomes. The National Cancer Data Base (NCDB) was used to retrieve patients with biopsy-proven IMPC from 2007 to 2012. Only patients with known HR and HER2 status were included. Cox multivariate regression was used to determine prognostic factors. In total, 865 patients were included; median follow-up was 2.5 years. Overall, 651 patients (75.3%) had HR + HER2- disease, 128 (14.8%) had HR + HER2+ disease, 41 (4.7%) had HR-HER2 + disease, and 45 (5.2%) had triple negative disease. Patients with triple negative disease were more likely to have poorly differentiated histology (66.7%), lymphovascular invasion (73.3%), stage 3 disease (37.8%), undergone mastectomy (68.9%), and positive surgical margins (15.6%). On Cox multivariate regression, those with triple negative disease had worse overall survival (hazard ratio [HR] 7.28, P < 0.001). Other adverse prognostic factors included African-American descent (HR 2.24, P = 0.018), comorbidity score of 1 (HR 2.50, P = 0.011), comorbidity score ≥2 (HR 3.27, P = 0.06), and ≥3 positive lymph nodes (HR 3.23, P = 0.007). Similar to invasive ductal carcinoma, triple negative disease in IMPC results in worse survival outcomes. This is the largest and first study to characterize molecular status (including HER2 status) in patients with IMPC and its impact on survival outcomes.
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Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Carcinoma Papilar/mortalidad , Carcinoma Papilar/patología , Carcinoma Ductal de Mama/mortalidad , Carcinoma Ductal de Mama/patología , Femenino , Humanos , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Receptor ErbB-2 , Sistema de Registros , Estudios Retrospectivos , Análisis de SupervivenciaRESUMEN
BACKGROUND: Breast cancer has been considered not highly immunogenic, and few patients benefit from current immunotherapies. However, new strategies are aimed at changing this paradigm. In the present study, we examined the in vivo activity of a humanized anti-programmed cell death protein 1 (anti-PD-1) antibody against triple-negative breast cancer (TNBC) patient-derived xenograft (PDX) tumor models. METHODS: To circumvent some of the limitations posed by the lack of appropriate animal models in preclinical studies of immunotherapies, partially human leukocyte antigen-matched TNBC PDX tumor lines from our collection, as well as human melanoma cell lines, were engrafted in humanized nonobese diabetic/severe combined immunodeficiency IL2Rγnull (hNSG) mice obtained by intravenous injection of CD34+ hematopoietic stem cells into nonlethally irradiated 3-4-week-old mice. After both PDXs and melanoma cell xenografts reached ~ 150-200 mm3, animals were treated with humanized anti-PD-1 antibody or anti-CTLA-4 and evaluated for tumor growth, survival, and potential mechanism of action. RESULTS: Human CD45+, CD20+, CD3+, CD8+, CD56+, CD68+, and CD33+ cells were readily identified in blood, spleen, and bone marrow collected from hNSG, as well as human cytokines in blood and engrafted tumors. Engraftment of TNBC PDXs in hNSG was high (~ 85%), although they grew at a slightly slower pace and conserved their ability to generate lung metastasis. Human CD45+ cells were detectable in hNSG-harbored PDXs, and consistent with clinical observations, anti-PD-1 antibody therapy resulted in both a significant reduction in tumor growth and increased survival in some of the hNSG PDX tumor lines, whereas no such effects were observed in the corresponding non-hNSG models. CONCLUSIONS: This study provides evidence associated with anti-PD-1 immunotherapy against TNBC tumors supporting the use of TNBC PDXs in humanized mice as a model to overcome some of the technical difficulties associated with the preclinical investigation of immune-based therapies.
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Anticuerpos Monoclonales Humanizados/farmacología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Neoplasias de la Mama Triple Negativas/terapia , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Animales , Citocinas/sangre , Citocinas/inmunología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Inmunoterapia/métodos , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Receptor de Muerte Celular Programada 1/inmunología , Neoplasias de la Mama Triple Negativas/sangre , Neoplasias de la Mama Triple Negativas/inmunología , Carga Tumoral/efectos de los fármacos , Carga Tumoral/inmunologíaRESUMEN
PURPOSE: Aberrant activation of the PI3K pathway has been implicated in resistance to HER2-targeted therapy, but results of clinical trials are confounded by the co-administration of chemotherapy. We investigated the effect of perturbations of this pathway in breast cancers from patients treated with neoadjuvant anti-HER2-targeted therapy without chemotherapy. PATIENTS AND METHODS: Baseline tumor samples from patients with HER2-positive breast cancer enrolled in TBCRC006 (NCT00548184), a 12-week neoadjuvant clinical trial with lapatinib plus trastuzumab [plus endocrine therapy for estrogen receptor (ER)-positive tumors], were assessed for PTEN status by immunohistochemistry and PIK3CA mutations by sequencing. Results were correlated with pathologic complete response (pCR). RESULTS: Of 64 evaluable patients, PTEN immunohistochemistry and PIK3CA mutation analysis were performed for 59 and 46 patients, respectively. PTEN status (dichotomized by H-score median) was correlated with pCR (32% in high PTEN vs. 9% in low PTEN, p = 0.04). PIK3CA mutations were identified in 14/46 tumors at baseline (30%) and did not correlate with ER or PTEN status. One patient whose tumor harbored a PIK3CA mutation achieved pCR (p = 0.14). When considered together (43 cases), 1/25 cases (4%) with a PIK3CA mutation and/or low PTEN expression levels had a pCR compared to 7/18 cases (39%) with wild-type PI3KCA and high PTEN expression levels (p = 0.006). CONCLUSION: PI3K pathway activation is associated with resistance to lapatinib and trastuzumab in breast cancers, without chemotherapy. Further studies are warranted to investigate how to use these biomarkers to identify upfront patients who may respond to anti-HER2 alone, without chemotherapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Fosfatidilinositol 3-Quinasa Clase I/genética , Fosfohidrolasa PTEN/genética , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Lapatinib , Persona de Mediana Edad , Mutación , Terapia Neoadyuvante/efectos adversos , Quinazolinas/administración & dosificación , Quinazolinas/efectos adversos , Receptor ErbB-2/genética , Trastuzumab/administración & dosificación , Trastuzumab/efectos adversosRESUMEN
Bromodomain and extraterminal (BET) proteins are epigenetic "readers" that recognize acetylated histones and mark areas of the genome for transcription. BRD4, a BET family member protein, has been implicated in a number of types of cancer, and BET protein inhibitors (BETi) are efficacious in many preclinical cancer models. However, the drivers of response to BETi vary depending on tumor type, and little is known regarding the target genes conveying BETi activity in triple-negative breast cancer (TNBC). Here, we show that BETi repress growth of multiple in vitro and in vivo models of TNBC by inducing two terminal responses: apoptosis and senescence. Unlike in other cancers, response to BETi in TNBC is not dependent upon suppression of MYC Instead, both end points are preceded by the appearance of polyploid cells caused by the suppression of Aurora kinases A and B (AURKA/B), which are critical mediators of mitosis. In addition, AURKA/B inhibitors phenocopy the effects of BETi. These results indicate that Aurora kinases play an important role in the growth suppressive activity of BETi in TNBC. Elucidating the mechanism of response to BETi in TNBC should 1) facilitate the prediction of how distinct TNBC tumors will respond to BETi and 2) inform the rational design of drug combination therapies.
Asunto(s)
Antineoplásicos/uso terapéutico , Aurora Quinasa A/antagonistas & inhibidores , Aurora Quinasa B/antagonistas & inhibidores , Mama/efectos de los fármacos , Proteínas Nucleares/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Factores de Transcripción/antagonistas & inhibidores , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Aurora Quinasa A/metabolismo , Aurora Quinasa B/metabolismo , Mama/metabolismo , Mama/patología , Proteínas de Ciclo Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Proteínas Nucleares/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Factores de Transcripción/metabolismo , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
BACKGROUND: A key challenge to mining electronic health records for mammography research is the preponderance of unstructured narrative text, which strikingly limits usable output. The imaging characteristics of breast cancer subtypes have been described previously, but without standardization of parameters for data mining. METHODS: The authors searched the enterprise-wide data warehouse at the Houston Methodist Hospital, the Methodist Environment for Translational Enhancement and Outcomes Research (METEOR), for patients with Breast Imaging Reporting and Data System (BI-RADS) category 5 mammogram readings performed between January 2006 and May 2015 and an available pathology report. The authors developed natural language processing (NLP) software algorithms to automatically extract mammographic and pathologic findings from free text mammogram and pathology reports. The correlation between mammographic imaging features and breast cancer subtype was analyzed using one-way analysis of variance and the Fisher exact test. RESULTS: The NLP algorithm was able to obtain key characteristics for 543 patients who met the inclusion criteria. Patients with estrogen receptor-positive tumors were more likely to have spiculated margins (P = .0008), and those with tumors that overexpressed human epidermal growth factor receptor 2 (HER2) were more likely to have heterogeneous and pleomorphic calcifications (P = .0078 and P = .0002, respectively). CONCLUSIONS: Mammographic imaging characteristics, obtained from an automated text search and the extraction of mammogram reports using NLP techniques, correlated with pathologic breast cancer subtype. The results of the current study validate previously reported trends assessed by manual data collection. Furthermore, NLP provides an automated means with which to scale up data extraction and analysis for clinical decision support. Cancer 2017;114-121. © 2016 American Cancer Society.
Asunto(s)
Neoplasias de la Mama/patología , Algoritmos , Neoplasias de la Mama/metabolismo , Minería de Datos/métodos , Sistemas de Apoyo a Decisiones Clínicas , Humanos , Mamografía/métodos , Persona de Mediana Edad , Procesamiento de Lenguaje Natural , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Programas InformáticosRESUMEN
Mutations in PIK3CA, the gene encoding the p110α catalytic subunit of phosphoinositide 3-kinase (PI3K) have been shown to transform human mammary epithelial cells (MECs). These mutations are present in all breast cancer subtypes, including basal-like breast cancer (BLBC). Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we identified 72 protein expression changes in human basal-like MECs with knock-in E545K or H1047R PIK3CA mutations versus isogenic MECs with wild-type PIK3CA. Several of these were secreted proteins, cell surface receptors or ECM interacting molecules and were required for growth of PIK3CA mutant cells as well as adjacent cells with wild-type PIK3CA. The proteins identified by MS were enriched among human BLBC cell lines and pointed to a PI3K-dependent amphiregulin/EGFR/ERK signaling axis that is activated in BLBC. Proteins induced by PIK3CA mutations correlated with EGFR signaling and reduced relapse-free survival in BLBC. Treatment with EGFR inhibitors reduced growth of PIK3CA mutant BLBC cell lines and murine mammary tumors driven by a PIK3CA mutant transgene, all together suggesting that PIK3CA mutations promote tumor growth in part by inducing protein changes that activate EGFR.
Asunto(s)
Neoplasias de la Mama/genética , Receptores ErbB/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Mutación/genética , Comunicación Paracrina , Fosfatidilinositol 3-Quinasas/genética , Transducción de Señal , Anfirregulina/metabolismo , Animales , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cromatografía Liquida , Fosfatidilinositol 3-Quinasa Clase I , Supervivencia sin Enfermedad , Regulación hacia Abajo/efectos de los fármacos , Factor de Crecimiento Epidérmico/farmacología , Receptores ErbB/antagonistas & inhibidores , Matriz Extracelular/efectos de los fármacos , Matriz Extracelular/metabolismo , Femenino , Humanos , Ratones Desnudos , Proteínas de Neoplasias/metabolismo , Comunicación Paracrina/efectos de los fármacos , Unión Proteica/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteómica , Transducción de Señal/efectos de los fármacos , Espectrometría de Masas en Tándem , Regulación hacia Arriba/efectos de los fármacosRESUMEN
We previously described a gene signature for breast cancer stem cells (BCSCs) derived from patient biopsies. Selective shRNA knockdown identified ribosomal protein L39 (RPL39) and myeloid leukemia factor 2 (MLF2) as the top candidates that affect BCSC self-renewal. Knockdown of RPL39 and MLF2 by specific siRNA nanoparticles in patient-derived and human cancer xenografts reduced tumor volume and lung metastases with a concomitant decrease in BCSCs. RNA deep sequencing identified damaging mutations in both genes. These mutations were confirmed in patient lung metastases (n = 53) and were statistically associated with shorter median time to pulmonary metastasis. Both genes affect the nitric oxide synthase pathway and are altered by hypoxia. These findings support that extensive tumor heterogeneity exists within primary cancers; distinct subpopulations associated with stem-like properties have increased metastatic potential.